Whole body glucose homeostasis is of critical importance and failure to properly regulate blood glucose is associated with or causes a myriad of health problems. There is controversy as to which of the many proposed glucose-sensing sites are most important in responding to acute changes in blood glucose. Recently the carotid bodies have emerged as a potentially important site in blood glucose regulation. However, the role of the carotid bodies in regulating whole body glucose homeostasis in humans has undergone minimal exploration. Therefore we aim to test the overall hypothesis that carotid bodies play an integral role in blood glucose sensing and regulation. By using euglycemic and hypoglycemic glucose clamps in conscious human subjects with intact and denervated carotid bodies, we will examine the effect of altered oxygen saturation (both hypoxic and hyperoxic) on whole body glucose homeostasis. Specifically, we will: 1) perform hyperinsulinemic hypoglycemic glucose clamps during normoxia and hyperoxia;a maneuver that should suppress the ability of type 1 glomus cells in the carotid bodies to sense hypoglycemia and therefore will limit the counterregulatory response to hypoglycemia, 2) perform hyperinsulinemic euglycemic glucose clamps during normoxia and hypoxia a maneuver that should stimulate the type 1 glomus cells in the carotid bodies and reduce glucose disappearance and insulin suppression of glucose production in spite of euglycemia and hyperinsulinemia, and 3) compare the physiological responses to hyperinsulinemic hypoglycemic glucose clamps in patients who have undergone bilateral carotid body denervation for the treatment of glomus tumor. PUBLIC HEALTH RELEVANCE: In the interest of public health concerns such as diabetes, sleep apnea, chronic obstructive pulmonary disease, and the metabolic syndrome, this study will investigate the possibility of a common mechanism for patients that have dysfunction in both glucose handling and ventilation. By examining the role of the carotid body chemoreceptors as multi-modal receptors that simultaneously sense blood glucose levels and oxygen, we will determine whether the carotid bodies play a role as an integrated sensor that influences both metabolism and ventilation in healthy humans.